Fig. 2.

Dual pH-responsive polymer-Dox conjugates (mPEG-b-PAEP-Cya-Hyd-DOX-DA) self-assemble into negatively charged micelles in water (1). When the micelle is exposed to the acidic tumor microenvironment (pH ~6.8), the negatively-charged portion of the polymer is cleaved off, revealing an amine group and rendering the particles positively charged (2). The positively charged micelles are more readily endocytosed by tumor cells (3, 4) and accumulate in endolysosomal compartments within the cell. At the even more acidic pH of endolysosomes (~5.5), the hydrazone bond is cleaved to release DOX, which diffuses into the nucleus of the cell (5). Reproduced with permission from Reference [54]. Copyright 2012, American Chemical Society.